Apoptosis is a form of programmed cell death and is evolutionarily conserved. Apoptosis plays an important role in the nervous system both during development and in homeostasis of adults. Inappropriate apoptosis may contribute to various neurodegenerative conditions including stroke, epilepsy, Down's syndrome, Parkinson's disease, Huntington's disease, ALS, and Alzheimer's disease. Hence, elucidation of mechanisms that regulate neuronal apoptosis is of fundamental importance for neurobiology and may ultimately contribute to the development of pharmacological interventions and clinical strategies for treatment of various neurodegenerative disorders. Neuronal activity and neurotrophins are critical for the differentiation, survival, and adaptive responses of neurons both during development and in the adult brain. Activation of the extracellular signal regulated kinases (ERK) 1 and 2 by neurotrophins, Ca2+ and cAMP have been strongly implicated in these processes. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, EGF stimulation of ERK5 is blocked by the MEK inhibitors, PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in neurons have not been reported. Our preliminary data suggest that neurotrophins including BDNF activated ERK5 in primary cultured cortical neurons. We hypothesize that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from ERK1/2 in neurons. We also hypothesize that ERK5 has unique physiological functions in the central nervous system (CNS). The overall objective of this proposal is to define the signal transduction pathway for ERK5 activation in primary cultured neurons, and the role for the ERK5 pathway in promoting neuronal survival. Cortical neurons were chosen because cerebral cortex is important for higher order learning and memory, and neurons in the cortex are frequently damaged in neurodegenerative diseases.